Kurt R. Weiss, MD is a musculoskeletal oncologist in the University of Pittsburgh Department of Orthopaedic Surgery, Division of Musculoskeletal Oncology. Dr. Weiss has trained at some of the most prestigious clinical centers in North America including the Universities of Pittsburgh Toronto. Besides these clinical accomplishments, Dr. Weiss is also the recipient of a rich exposure to basic science research. He has been involved in molecular and cell biology research since 1994, and oncology research since 1999. He has worked with sarcoma research experts at the MD Anderson Cancer Center and the National Cancer Institute as well as the Universities of Toronto and Pittsburgh. Dr. Weiss's passion to advance the field of translational sarcoma research is necessarily the product of his personal history as a survivor of metastatic osteosarcoma (OS). His journey with cancer included participation in a Phase II clinical trial for recurrent OS metastases; an experience that shaped his goals and taught him that translational sarcoma research is both possible and essential. Dr. Weiss has also experienced the difficulties of sarcoma surgery which culminated in the amputation of his right leg. This permanent disability has not lessened his desire to discover novel treatments that address the unmet problem of sarcoma pulmonary metastases. His short-term goal is to develop skills as a translational scientist that will enable him to build a vigorous, comprehensive sarcoma research program at the University of Pittsburgh. His long-term goal is to translate bench top discoveries into clinical solutions for patients with metastatic sarcoma. Despite his unique personal, clinical, and scientific background, Dr. Weiss understands that his knowledge and skills are far from complete. In pursuit of his goal to develop an independent translational sarcoma research program, he proposes the following: AIM I- PROFESSIONAL DEVELOPMENT: Dr. Weiss recognizes the areas in which he requires additional development in order to become a well-rounded translational oncologist. If granted a K08 award, Dr. Weiss will pursue didactic courses in biostatistics, proteomics, and signal transduction. He will attend courses and workshops on grant-writing and will submit frequent grant proposals. He will communicate his scientific findings at national and international meetings. Regularly scheduled meetings with his mentor, co-mentors, and collaborators will enhance professional relationships across multiple clinical and scientific disciplines. AIM II- LABORATORY DEVELOPMENT: Dr. Weiss will expand upon his preliminary findings on OS metastatic disease, and use this research as a pathway toward understanding metastatic potential in other sarcomas. OS is the most common primary malignancy of bone. Despite aggressive chemotherapeutic and surgical treatments, overall survival is only 60-70%. Patients who are diagnosed with metastatic OS or develop metastases during the course of their treatment have particularly poor prognoses with survival rates of 15-30%. These statistics have not improved in over a generation. For patients with OS specifically and sarcoma in general, the problem of metastatic disease remains unsolved. As current treatment paradigms have declared themselves unsuccessful for patients with metastases, advancement in sarcoma treatment demands a refined understanding of the mechanisms that govern tumor growth and metastasis. Novel, biologically intelligent treatment strategies are required to improve the prognoses of patients with OS and other sarcomas. Dr. Weiss has published that that OS cell populations with differing metastatic potentials express and produce different levels of growth factors, and the inhibition of these growth factors affects OS cell metastatic behavior. He has recently discovered that stem cell-associated factors, specifically aldehyde dehydrogenase (ALDH) and Notch1, are differentially expressed in OS cells with different metastatic phenotypes. The inhibition of these factors also affects the in vitro metastatic phenotypes of OS cells. Dr. Weiss therefore proposes to interrogate clinically relevant ALDH and Notch1 inhibitors both in vitro and in vivo with the murine model of metastatic OS. These experiments will assess the feasibility of ALDH and Notch1 inhibition as specific anti- metastatic therapies for OS. In the past year, Dr. Weiss and his clinical partners have instituted the Musculoskeletal Oncology Tumor Registry and Tissue Bank (MOTOR). This is an IRB-approved mechanism by which patients' clinical data are constantly gathered and correlated with the biological activity of their tumor cells. Dr. Weiss has already developed approximately fifteen novel cell lines from patients with various sarcoma histologic subtypes. This ever-expanding collection is an invaluable scientific resource that will allow Dr. Weiss to uncover common themes in the basic biology of sarcoma metastases, and enable him to test novel, targeted anti-metastatic treatments. The environment provided by the University of Pittsburgh, the University of Pittsburgh Medical Center, the Clinical and Translational Science Institute, and the University of Pittsburgh Cancer Institute could hardly be more conducive to these proposed projects. As part of his career development, Dr. Weiss will continue to cultivate relationships and collaborations within these institutions in order to build a vigorous and productive sarcoma translational research program.